Antibiotic-resistant
Gram-negative bacteria are emergent pathogens,
causing millions of infections worldwide. While there are several
classes of antibiotics that are effective against Gram-positive bacteria,
the outer membrane (OM) of Gram-negative bacteria excludes high-molecular-weight
hydrophobic antibiotics, making these species intrinsically resistant
to several classes of antibiotics, including polyketides, aminocoumarins,
and macrolides. The overuse of antibiotics such as β-lactams
has also promoted the spread of resistance genes throughout Gram-negative
bacteria, including the production of extended spectrum β-lactamases
(ESBLs). The combination of innate and acquired resistance makes it
extremely challenging to identify antibiotics that are effective against
Gram-negative bacteria. In this study, we have demonstrated the synergistic
effect of outer membrane-permeable cationic polyurethanes with rifampicin,
a polyketide that would otherwise be excluded by the OM, on different
strains of E. coli, including a clinically
isolated uropathogenic multidrug-resistant (MDR) E.
coli. Rifampicin combined with a low-dose treatment
of a cationic polyurethane reduced the MIC in E. coli of rifampicin by up to 64-fold. The compositions of cationic polyurethanes
were designed to have low hemolysis and low cell cytotoxicity while
maintaining high antibacterial activity. Our results demonstrate the
potential to rescue the large number of available OM-excluded antibiotics
to target normally resistant Gram-negative bacteria via synergistic
action with these cationic polyurethanes, acting as a novel antibiotic
adjuvant class.
Three-dimensional
(3D) printing offers the unprecedented ability
to create medical devices with complex architectures matched to the
patient’s anatomy. However, the development of 3D printable
synthetic polymers for biomedical applications has been relatively
slow. Here, we present the synthesis and characterization of a library
of single-component, undiluted, modular multifunctional polyesters
for extrusion-based direct-write 3D printing (EDP). The polyesters
were synthesized using carbodiimide-mediated polyesterification of
pendant functionalized diols and succinic acid and characterized using 1H NMR, gel permeation chromatography (GPC), differential scanning
calorimetry (DSC), and rheology. The rheology was characterized by
using small amplitude oscillatory shear rheology and at steady-state
shear flow conditions. The viscoelasticity of the polyesters was characterized
by plotting master curves using the time–temperature superposition
(TTS) principle, which were then validated by Van Gurp-Palmen and
Cole–Cole plots. The 3D printability of the polyesters was
assessed on the basis of several key parameters including the ability
to extrude as continuous filaments, retain the printed shape, form
multilayer constructs, and form bridge-spanning filaments without
significant sagging or collapse. The rheological characterization
suggests that the polyesters are unentangled melts that facilitate
printing at ambient temperatures without the use of external additives
or solvents. The presence of supramolecular interactions inducing
pendant functional groups forms a temporary, physical cross-link-like
network that enables 3D shape retention. The insights from this study
will further assist in the design and characterization of 3D printable
polymer melts for biomedical applications and standardizing the assessment
of polymer 3D printability.
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